Summary of work: Although the incidence of cancer increases with age, tumors of the prostate, breast, and ovary grow more slowly and progression is less aggressive in the elderly, perhaps because of changes in tumor vasculature. However, adequate animal models to study these processes have not been available. Several transplantable mouse tumor models are being used to identify factors which may contribute to inhibition of tumor growth in aged animals. One of these tumors is being used to study vascular sprouting of explants within basement membrane gels in culture. We have found that inhibitors of collagenases (minocycline) and microtubule- stabilizing drugs inhibit sprouting and that sprouting is significantly inhibited when tumors are grown in aged mice. We have continued our studies examining endothelial cell apopotosis and have used an immortal human umbilical vein endothelial cell. These cells undergo apoptosis in response to taxol or etoposide, a process which can be inhibited by pre-treatment with estradiol or by growing the cells on basement membrane extracts. Protection from apoptosis was associated with the induction of the p21 cell cycle inhibitor and expression of estrogen receptors. Using mobility-shift assays, NFkB activity was found to be elevated in cells protected from cell death by extracellular matrix binding. In fact, NFkB activation was found to be essential for continued survival and differentiation of these cells since anti-sense oligonucleotide treatment inhibited endothelial cell differentiation. These results suggest that these immortal endothelial cells retain many features of normal vascular cells and, therefore, may be useful to study the role of chemotherapeutic agents and hormones in endothelial cell apoptosis and differentiation.